Feb.18th, 2015
IABS, PMDA and JST joint Symposium
Scientific Points to Consider:
Starting Cells, Other Raw Materials,
Manufacturing-Related Substances and
Non-cellular Components Constituting
the Complex Final Products
Daisuke MAEDA, PhD
Office of Cellular and Tissue-based Products
Pharmaceuticals and Medical Devices Agency (PMDA), Japan
Disclaimer:
The views and opinions expressed here are those of the
presenter and do not necessarily represent those of PMDA.
Pharmaceuticals and Medical Devices Agency
1
Contents
1. Overviews of materials for manufacturing
2. Starting materials
3. Other raw materials and manufacturingrelated substances
4. Non-cellular components constituting the
complex final products
Pharmaceuticals and Medical Devices Agency
2
Contents
1. Overviews of materials for manufacturing
2. Starting materials
3. Other raw materials and manufacturingrelated substances
4. Non-cellular components constituting the
complex final products
Pharmaceuticals and Medical Devices Agency
3
Manufacturing Process of CTPs
Collection of Cell Source
Starting cells
Raw Materials
Culture (amplification)
Raw Materials
Cell Bank/ Cell Stock
Culture (differentiation)
Manufacturing-Related Substances
Raw Materials
Manufacturing-Related Substances
Filling
(Cryopreservation)
Excipients
Manufacturing-Related Substances
Final Product
Pharmaceuticals and Medical Devices Agency
4
Case of Autologous Cultured Epidermis ＪＡＣＥ
(MAA: 29th Oct. 2007 )
Collection of Cell Source
Patient’s skin
Starting cells
Culture (amplification)
Cell Stock
Culture flask
・・・ManufacturingRelated Substances
Filling
Carrier,
Cover sheet
・・・ManufacturingRelated Substances
Final Product
Pharmaceuticals and Medical Devices Agency
･･･Source Tissues
Protease/ collagenase
Culture media
FBS
Feeder cells
Recombinant insulin
Human EGF
Cholera toxin
Antibiotics
Trypsin
Dulbecco's PBS
Storage buffer
Raw
Materials
･･･Excipients
Excerpt from Review Report on JACE,
http://www.pmda.go.jp/english/service/p
df/medical_devices/jace_oct2007_e.pdf
5
Categorization of Materials Used in Manufacturing
Raw Materials
Human and
animal-derived
Manufacturing-Related
substances
Non animal-derived
Starting materials
Tissues, Cells
FBS, Human Serum,
HSA, Feeder Cells,
Trypsin, Heparin
Culture media
Recombinants
(animal-free)
Antibiotics
D-PBS
Culture dishes/ flasks,
Columns, Filters,
Vessels, Tubing, Bags
Excipients/ Non-cellular components
of final products
Collagen matrix
Storage buffer, Scaffolds, Sponge,
Support membranes, Fibers
Pharmaceuticals and Medical Devices Agency
6
What’s “Ancillary Materials” ?

No Japanese equivalent for “Ancillary Material” as a legal term.

Ancillary materials (AMs)
include a wide variety of raw materials and materials used in
process,
are used to ensure the safety, effectiveness, and consistency of
the final product,
come into contact with the cells or tissues during
manufacturing,
are not intended to be part of the final product formulation.
Materials or components that are intended to be in the final
product dosage form are not AMs.





→ USP General Information <1043> Ancillary Materials
Pharmaceuticals and Medical Devices Agency
7
Categorization of Materials Used in Manufacturing
Raw Materials
Human and
animal-derived
Manufacturing-Related
substances
Non animal-derived
Starting materials
Tissues, Cells
Ancillary materials
FBS, Human Serum,
HSA, Feeder Cells,
Trypsin, Heparin
Culture media
Recombinants
(Animal-free)
Antibiotics
D-PBS
Culture dishes/ flasks,
Columns, Filters,
Vessels, Tubing, Bags
Excipients/ Non-cellular components
of final products
Collagen matrix
Storage buffer, Scaffolds, Sponge,
Support membranes, Fibers
Pharmaceuticals and Medical Devices Agency
8
Assurance of Product Quality
Design
Quality
Procedure
Process
Material
Equipment
Product
Quality
Quality
Management
Quality Risk Management /
Knowledge Control


Product Quality is affected by various factors.
Better understanding the variables in the process, leads to
good quality control.
Pharmaceuticals and Medical Devices Agency
9
Quality of Materials for Manufacturing
in the Control Strategy
ICH-Q10
Input
Manufacturing process
Control
Procedural controls
Output
on end-product
• Sequence of
• Release testing
processing steps
Output
Control
on material attributes
• Starting cells
• Raw materials
Input
• Excipients
• Primary packaging
materials
etc.
In-process control
Parametric control
In-process control
In-process testing
Pharmaceuticals and Medical Devices Agency
10
Contents
1. Overviews of materials for manufacturing
2. Starting materials
3. Other raw materials and manufacturingrelated substances
4. Non-cellular components constituting the
complex final products
Pharmaceuticals and Medical Devices Agency
11
Points to Consider for Starting Materials
Source and Selection of Human Cells/
Donors
2. Donor Eligibility
・Test for the infectious diseases
・Information about clinical history
3. Collection, Storage, and Transport of
Cells and Tissues
1.
Pharmaceuticals and Medical Devices Agency
12
1. Source and Selection of Human Cells/ Donors
 Characteristics in biological structure/function of the
starting cells/tissue should be provided by
appropriately selected parameters such as
・morphological characteristics
・growth characteristics
・biochemical and immunological parameters
・HLA typing
・other relevant genotypic or phenotypic markers.
 Reasons for selection of the cell/tissue should be
provided.
Pharmaceuticals and Medical Devices Agency
13
2. Donor Eligibility Criteria

When collecting human cell / tissue material,
depending on the purpose of their use, relevant
bacterial, fungal and viral infections have been
denied through interviews, screening tests.

The test parameters and methods used should be
justified in light of the latest knowledge of infectious
diseases, etc..

The donor’s clinical history of having received
blood transfusion or transplantation must be taken
into consideration when determining donor
eligibility.
Pharmaceuticals and Medical Devices Agency
14
2. Donor Eligibility Criteria (continued)

According to the test parameters and
methods, the re-testing and other infection
controls at the right time should been made,
taking into consideration the window period.

However, it does not necessarily require a
donor screening when the donor is the
same person as the recipient (autologous).
Pharmaceuticals and Medical Devices Agency
15
Autologous C/T vs Allogeneic C/T
Autologous Human Cells/Tissues
Infectious
status of donor, including
infections of HBV, HCV, HIV, and
HTLV.
Risk
of viral replication or re-activation
in manufacturing processes
Robust
process control to minimize
unevenness of “custom-made”
products
Limited
amounts of samples for
quality evaluation of products
Pharmaceuticals and Medical Devices Agency
Allogenic Human Cells/Tissues
History,
source, derivation
Donor screening/testing and donor eligibility
(compatibility with donor qualification criteria,
including ethical and medical aspects;
freedom from the presence of HBV, HCV,
HIV, HTLV and parvovirus B19 by screening
and testing; exclusion of potential infection of
CMV, EBV and WNV by testing; clinical
history; experience of blood transfusion or
implanting; genetic variants etc.)
Records of donor
Derivation of cell strain
Cell banking
Viral assays at the final product level
Immunological relevance
16
2. Donor Eligibility Criteria (continued)
Donor Recordkeeping

The records of donors should be maintained and
stored so as to verify information required to
secure safety of the cell and tissue as materials.

For each experimental sample of the donor and
the patient, the content of information and its
storage measure may depend on the intended
use.
Pharmaceuticals and Medical Devices Agency
17
3. Collection, Storage, and Transportation
of Cells and Tissues
(1) Eligibility of medical professionals and institutions
collecting the samples
(2) Suitability of the sampling site and method
(3) Interviews or tests to ensure donor safety
(4) Informed consent for donors
(5) Protection of donor privacy
(6) Storage methods and measures to prevent
erroneous sampling (mix-up)
(7) Transportation methods
(8) Preparation of records for (1)-(7) and record-keeping
procedures
Pharmaceuticals and Medical Devices Agency
18
Contents
1. Overviews of materials for manufacturing
2. Starting materials
3. Other raw materials and manufacturingrelated substances
4. Non-cellular components constituting the
complex final products
Pharmaceuticals and Medical Devices Agency
19
Categorization of Materials Used in Manufacturing
Raw Materials
Human and
animal-derived
Manufacturing-Related
substances
Non animal-derived
Starting materials
Tissues, Cells
Ancillary materials
FBS, Human Serum,
HSA, Feeder Cells,
Trypsin, Heparin
Culture media
Recombinants
(animal-free)
Antibiotics
D-PBS
Culture dishes/ flasks,
Columns, Filters,
Vessels, Tubing, Bags
Excipients/ Non-cellular components
of final products
Collagen matrix
Storage buffer, Scaffolds, Sponge,
Support membranes, Fibers
Pharmaceuticals and Medical Devices Agency
20
Impact of AMs on Quality and Safety of CTPs







The quality of AMs is very important to ensure the stability,
safety, potency and consistency of CTPs as following;
The precise mechanism by which an AM exerts its effect may
not be known.
The impact of variations of the AM on the quality and safety
of the final product may not be understood.
AMs of human or animal origin may present an infectious
disease transmission risk.
Some AMs may elicit an immune reaction to the human.
Some AMs have toxic properties.
The risks attributed to the quality of AMs on the quality and
safety of CTPs are often increased due to the limited ability
to conduct extensive in-process and release tests.
Pharmaceuticals and Medical Devices Agency
21
Qualification



Whenever possible, it is preferable to use AMs that
are approved as drugs because they are well
characterized, have an established toxicological
profile, and are manufactured according to controlled
and documented procedures.
Conversely, the AM “for research use only” may not
satisfy the level of qualification necessary for use in
the production of a therapeutic product.
In either case, CTPs should be developed with
comprehensive and scientifically sound qualification
plans to ensure the traceability, consistency,
suitability, purity, and safety of the AM.
Pharmaceuticals and Medical Devices Agency
22
USP’s risk-based approach
USP General Information
<1043> Ancillary Materials for Cell, Gene, and Tissue-Engineered Products
Tier
Risk
Properties of materials
1
Low
highly qualified materials with intended use as
therapeutic drugs or biologics, medical devices, or
implantable materials (e.g. heparin for injection)
2
Low
well-characterized materials with intended use as AMs,
produced in compliance with GMPs
3
Moderate
materials not intended for use as AMs (frequently
produced for in vitro diagnostic use or reagent-grade
materials)
4
High
High-risk materials(e.g., FBS, animal-derived(including
human) extracts, animal or human cells used as feeder
layers, chemical entities with known toxicities)
Pharmaceuticals and Medical Devices Agency
23
USP’s risk-based approach (continued)
F. Atouf et al, BioProcess International 11(8) 12-21, 2013
Pharmaceuticals and Medical Devices Agency
24
Human and Animal-Origin Raw Materials
(except Starting Materials)
 The source is to be clarified.
 Efforts are to be made to reduce the risk of infection
for adventitious agents;
 minimize their amounts used
 explore alternative substances or sources (i.e., plant
or chemically synthesized).
 ensure donor’s and donor animal’s health
 The manufacturing process is to be evaluated on the
potentials to eliminate/inactivate adventitious agents
 Records in manufacturing are to be kept to ensure
their traceability.
Pharmaceuticals and Medical Devices Agency
25
Selection of Bovine Serum (as an example)





Types of bovine serum
Origin(country, strain)
Vendor
Grade
Lot size available
Pharmaceuticals and Medical Devices Agency
26
Guidelines for Bovine Serum
EMA
GL on the use of bovine serum in the manufacture of human
biological medicinal products(30 May 2013, EMA/CHMP/
BWP/457920/2012 rev.1)

US Pharmacopoeia
<1043> Ancillary Materials
<1024> Bovine Serum
<90> FBS Quality Attributes and Functionality Tests

Pharmaceuticals and Medical Devices Agency
27
Other Raw Materials
•
Culture media (composition)
•
Recombinant growth factors, cytokines (animal-
free)
•
Monoclonal antibodies for cell sorting/purification
•
Antibiotics
Pharmaceuticals and Medical Devices Agency
28
Selection of Raw Materials

Select the materials on a risk-based
approach based on own/existing knowledge
for the product, referring to literatures and
GLs, and then,

Provide the rationale for their selection and
the quality control to your competent
authorities, and consult with them.
Pharmaceuticals and Medical Devices Agency
29
Manufacturing- Related Substances
•
•
•
•
Culture dishes
Columns
Filters
Bags
• Leacheables / Extractables
• Foreign matter
Pharmaceuticals and Medical Devices Agency
30
Contents
1. Overviews of materials for manufacturing
2. Starting materials
3. Other raw materials and manufacturingrelated substances
4. Non-cellular components constituting the
complex final products
Pharmaceuticals and Medical Devices Agency
31
Categorization of Materials Used in Manufacturing
Raw Materials
Human and
animal-derived
Manufacturing-Related
substances
Non animal-derived
Starting materials
Tissues, Cells
Ancillary materials
FBS, Human Serum,
HSA, Feeder Cells,
Trypsin, Heparin
Culture media
Recombinants
(animal-free)
Antibiotics
D-PBS
Culture dishes/ flasks,
Columns, Filters,
Vessels, Tubing, Bags
Excipients/ Non-cellular components
of final products
Collagen matrix
Storage buffer, Scaffolds, Sponge,
Support membranes, Fibers
Pharmaceuticals and Medical Devices Agency
32
Points to Consider on Non-cellular Components
1. In case of bio-absorbable materials, perform the
necessary tests for the safety of the degradation
products.
2. Evaluate the consequences of interactions between
non-cellular components and cells:
(a) any deleterious effects on the function, growth
activity, or stability of the cells
(b) any potential mutation, transformation, and/or
dedifferentiation of the cells
(c) no loss of the expected properties of the non-cellular
components
Pharmaceuticals and Medical Devices Agency
33
Take-home Messages

Quality of the materials is one of the critical
factors and should be determined on caseby-case basis approach depending on the
characteristics of the product and its control
strategy as a whole.
Pharmaceuticals and Medical Devices Agency
34
Take-home Messages (continued)
As for starting materials;
 Donor eligibility criteria are key elements;
infectious agents.
 Reasons for selection of the cell/tissue should be
provided with its desired/ targeted cell profile.
 The characteristics of their structure and
biological function should be shown.
 Appropriate handling and processing is required.
Pharmaceuticals and Medical Devices Agency
35
Take-home Messages (continued)
As for other materials;
 Adequacy of using other raw materials and
manufacturing-related substances should be
shown, and it is necessary to perform
appropriate quality control with defined
acceptance criteria.
 Non-cellular components constituting the final
products should be justified in term of the
quality and the safety of CTPs. Appropriate/
sufficient information should be collected and
provided.
Pharmaceuticals and Medical Devices Agency
36
PMDA Pharmaceutical Affairs Consultation
on R&D Strategy
Strategic Consultation
Clinical Use
Basic Research
Pharmaceuticals
and Medical
Devices
candidates
Quality
Study
NonClinical
Study
Consultation on quality or
toxicity study of biologics, or
cellular therapy products
Pharmaceuticals and Medical Devices Agency
Clinical
Trial
Innovative
Products
Consultation on
endpoints or sample size
of early clinical trial
37
Thank you
for your kind attention!
Pharmaceuticals and Medical Devices Agency
38